12-122232361-G-A

Variant names:

• chr12-122232361-G-A
• NM_022916.6:c.1676C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022916.6(VPS33A):​c.1676C>T​(p.Ala559Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS33A NM_022916.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88
• Publications: 0 publications found

Genes affected

VPS33A (HGNC:18179): (VPS33A core subunit of CORVET and HOPS complexes) This gene encodes a tethering protein and a core subunit of the homotypic fusion and protein sorting (HOPS) complex. The HOPS complex and a second endosomal tethering complex called the class C core vacuole/endosome tethering (CORVET) complex, perform diverse functions in endocytosis including membrane tethering, RabGTPase interaction, activation and proofreading of synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) assembly to drive membrane fusion, and endosome-to-cytoskeleton attachment. The HOPS complex controls endosome maturation as well as endosome traffic to the lysosome. This complex is essential for vacuolar fusion and is required for adaptor protein complex 3-dependent transport from the golgi to the vacuole. The encoded protein belongs to the Sec1/Munc18 (SM) family of SNARE-mediated membrane fusion regulators. Naturally occurring mutations in this gene are associated with a novel mucopolysaccharidosis-like disease. [provided by RefSeq, Apr 2017]

VPS33A Gene-Disease associations (from GenCC):

• mucopolysaccharidosis-plus syndrome

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000256861 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022916.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33A	NM_022916.6	MANE Select	c.1676C>T	p.Ala559Val	missense	Exon 13 of 13	NP_075067.2
	VPS33A	NM_001351018.2		c.1643C>T	p.Ala548Val	missense	Exon 13 of 13	NP_001337947.1
	VPS33A	NM_001351019.2		c.1628C>T	p.Ala543Val	missense	Exon 13 of 13	NP_001337948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33A	ENST00000267199.9	TSL:1 MANE Select	c.1676C>T	p.Ala559Val	missense	Exon 13 of 13	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1559C>T		non_coding_transcript_exon	Exon 12 of 16	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.1823C>T	p.Ala608Val	missense	Exon 14 of 14	ENSP00000439255.3	F5H2X5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.85		Gain of catalytic residue at A559 (P = 0.2501)
MVP		0.49
MPC		1.1
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.76
gMVP		0.95
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-122716908;